Regulation of PPAR gamma gene expression by nutrition and obesity in rodents
Regulation of PPAR gamma gene expression by nutrition and obesity in rodents
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DOI：
10.1172/jci118703
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发表时间：
1996-06-01
影响因子：
15.9
通讯作者：
Moller, DE
中科院分区：
文献类型：
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作者：
VidalPuig, A;JimenezLinan, M;Moller, DE
孤儿核受体，过氧化物酶体增殖物激活受体(PPAR)，参与调节脂肪特异性基因的表达和激活脂肪细胞的分化程序。在体内调节PPARγ基因表达的可能性尚不清楚。我们克隆了小鼠PPARγ基因的一部分，并建立了一种RNase保护实验，允许同时定量由PPAR Gamma基因编码的Gamma 1和Gamma 2亚型的mRNAs。用来检测肥胖基因产物脂肪细胞P2、瘦素和18S mRNAs的探针也被使用。在脂肪组织中，γ-1和γ-2mRNA均有大量表达。PPAR-Gamma 1在肝脏、脾和心脏也有较低水平的表达，而在骨骼肌中有较低水平的表达。在两种肥胖小鼠模型(金硫糖和ob/ob)中，脂肪组织中伽马1和伽马2的水平没有改变，但在毒素基因诱导的棕色脂肪消融解偶联蛋白白喉毒素A小鼠中，脂肪组织水平略有增加。粘贴(12-48小时)与脂肪组织中PPAR-γ2下降80%和PPAR-1mRNA水平下降50%相关。Western印迹分析显示禁食对降低脂肪组织中PPAR-γ蛋白水平有明显作用。在所有三种肥胖模型中，禁食对PPARγmRNAs的影响相似。在胰岛素治疗期间部分恢复的正常小鼠中，胰岛素缺乏(链脲佐菌素)糖尿病将脂肪组织伽马1和伽马2的表达抑制了75%。暴露于高脂饮食的正常小鼠的脂肪组织PPAR-Gamma 2mRNA水平增加了50%。在肥胖的解偶联蛋白白喉毒素A小鼠中，高脂饮食可诱导肝脏PPAR-γ2的表达。我们得出的结论是：(A)正常小鼠脂肪细胞中PPAR Gamma 2的mRNA表达最丰富，但在骨骼肌中可见较低水平的表达；(B)在三种肥胖模型中，只有一种肥胖模型中脂肪组织Gamma 1或Gam2的mRNA表达增加；(C)PPAR Gamma 1和Gamma 2的表达受到禁食和胰岛素缺乏性糖尿病的下调；(D)高脂饮食增加了(正常小鼠)脂肪组织中PPAR Gamma的表达，并诱导了(肥胖小鼠)肝脏中PPAR Gamma 2的mRNA表达。这些发现表明，在体内，PPARγmRNA水平的调节范围超过四倍，并为控制脂肪细胞的发育和功能提供了额外的调节水平。
The orphan nuclear receptor, peroxisome proliferator-activated receptor (PPAR) gamma, is implicated in mediating expression of fat-specific genes and in activating the program of adipocyte differentiation. The potential for regulation of PPAR gamma gene expression in vivo is unknown. We cloned a partial mouse PPAR gamma cDNA and developed an RNase protection assay that permits simultaneous quantitation of mRNAs for both gamma 1 and gamma 2 isoforms encoded by the PPAR gamma gene. Probes for detection of adipocyte P2, the obese gene product, leptin, and 18S mRNAs were also employed. Both gamma 1 and gamma 2 mRNAs were abundantly expressed in adipose tissue. PPAR gamma 1 expression was also detected at lower levels in liver, spleen, and heart; whereas, gamma 1 and gamma 2 mRNA were expressed at low levels in skeletal muscle. Adipose tissue levels of gamma 1 and gamma 2 were not altered in two murine models of obesity (gold thioglucose and ob/ob), but were modestly increased in mice with toxigene-induced brown fat ablation uncoupling protein diphtheria toxin A mice. Pasting (12-48 h) was associated with an 80% fall in PPAR gamma 2 and a 50% fall in PPAR gamma 1 mRNA levels in adipose tissue. Western blot analysis demonstrated a marked effect of fasting to reduce PPAR gamma protein levels in adipose tissue. Similar effects of fasting on PPAR gamma mRNAs were noted in all three models of obesity. Insulin-deficient (streptozotocin) diabetes suppressed adipose tissue gamma 1 and gamma 2 expression by 75% in normal mice with partial restoration during insulin treatment. Levels of adipose tissue PPAR gamma 2 mRNA were increased by 50% in normal mice exposed to a high fat diet. In obese uncoupling protein diphtheria toxin A mice, high fat feeding resulted in de novo induction of PPAR gamma 2 expression in liver. We conclude (a) PPAR gamma 2 mRNA expression is most abundant in adipocytes in normal mice, but lower level expression is seen in skeletal muscle; (b) expression of adipose tissue gamma 1 or gamma 2 mRNAs is increased in only one of the three models of obesity; (c) PPAR gamma 1 and gamma 2 expression is downregulated by fasting and insulin-deficient diabetes; and (d) exposure of mice to a high fat diet increases adipose tissue expression of PPAR gamma (in normal mice) and induces PPAR gamma 2 mRNA expression in liver (in obese mice). These findings demonstrate in vivo modulation of PPAR gamma mRNA levels over a fourfold range and provide an additional level of regulation for the control of adipocyte development and function.